Re: Egypt fears of bird flu mutation
Actually, H5N1 is much further along than most realize, and much more deadly than the 1918 pandemic strain. The details are fairly complex and the politics surrounding the science is without precedent, but the overall story is really quite straight forward. Influenza A has 8 gene segments which code for at least 11 genes. These genes produce proteins with various functions in the life cycle of the virus, which has to get into a cell, replicate, get out of a cell, spread within the host, and transmit to another host. Changes that affect each step can have significant effects on hosts, including death. With the right combinations of changes, H5N1 can be quite deadly, with case fatality rates was high as 100% (all reported infections in Egypt with HA M230I). Overall, the case fatality rate is closer to 70%, but that is still 10X the rate of the 1918 pandemic strain. Thus, if H5N1 is efficiently transmitted, 1918 will look like a walk in the park.
The "Asian" strain of H5N1 already has several changes in its 8 gene segments which have become fixed, or present in almost all isolates. The most well known change and the greatest contributor to pathology on domestic poultry, which is the criteria for distinguishing high path avian influenza (HPAI) from low path (LPAI).
To start an infection, influenza has to get into a cell, which involves cutting the H in half. This is done at the "cleavage site" and is done by molecular scissors that cut after a basic amino acid (R or K). Season flu has one R and cleavage is limited to enzymes in the respiratory tract, so season flu doesn't spread outside of the respiratory tract. HPAI has multiple basic amino acids (the classic cleavage site for H5N1 is RERRRKKR, so 7 of the 8 positions are an R or K), so it can be cleaved by multiple enzymes in multiple cell types, so H5N1 can spread beyond the respiratory tract, which is why patients can die from multi-organ failure and why H5N1 can be neurotropic (replicates in neurological cells such as the brain). The classical cleavage site of H5N1 was first identified in 1996 in a goose in Guangdong Province (adjacent to Hong Kong), so the H5N1 of concern is relatively new.
The discovery of the "guangdong goose" in 1996 was followed by the first reported human infections by H5N1, which were in Hong Kong in 1997. The H5N1 in patients (6 of 16 died) had the HA cleavage site described above, as well as a deletion (19 aa) in N. Deletions in N had also been associated with previous outbreaks in poultry (when it was called fowl plague disease). That version of H5N1 pretty much disappeared after all birds in Hong Kong were culled, but that N was quickly replaced by another N with a 20 aa deletion, which overlapped the 19 aa deletion, but was slightly downstream. This change has been described in the literature as appearing in the 2003/2004 explosion of H5N1 infections by the "Z genotype", but in reality, the 20 aa deletion has been reported in H5N1 in northern China in 1997, so it was flying around China long before it emerged in 2003/2004 in patient in Vietnam and Thailand. The 20 aa deletion in NA has now also become fixed in H5N1.
Another change is a 5 amino acid deletion in the NS gene segment. This change is also associated with a more lethal H5N1, which involves evasion of the host immune response. The 5 aa deletion in NS1 also appeared during the 2003/2004 outbreak and it too has become fixed in H5N1.
Another change in H5N1 is PB2 E627K. PB2 is one of the three polymerase genes involved with copying the influenza genetic information and position 627 comes in two forms. An E at that position is found in birds and the polymerase activity is highest at 41 C, the body temperature of birds. A K at that position changes the activity of the polymerase gene, which is then the highest at 33 C, which is close to the temperature of a human nose in the winter. Consequently, E627K is a "mammalian" change, that was first isolated from H5N1 from a bird at Qinghai Lake in May, 2005. That change has also become fixed in the Qinghai strain, which is transported and transmitted by long range migratory birds, and virtually all H5N1 north and west of China (including Europe, the Middle East, and Africa) is the Qinghai strain.
Thus, H5N1 has acquire several changes that increase its ability to cause lethal infections in birds and mammals. These changes above have become fixed in H5N1 in general, or in the case of PB2 E627K, the Qinghai strain in particular.
The ingredient missing from the recipe of a virulent pandemic H5N1 is efficient transmission from person to person. This is primarily controlled by the receptor binding domain in HA, which is a very small region on HA (including H5). A variety of changes in the receptor binding domain have been found, including S227N and M230I, which is adjacent to the receptor binding domain. Other changes have also been seen in H5N1 infected patients in the Middle East (Turkey, Azerbaijan, Iraq, Egypt), which is why outbreaks there are cause for concern, because H5N1 there also has E627K. These human cases in the Middle East also have a high case fatality rate, so small changes in the receptor binding domain need not cause a reduction in the case fatality rate.
The number of reported receptor binding changes in H5N1 continues to increase, causing concern that the combination of changes leading to a dramatic increase in transmission efficiency can happen almost instantly.
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